Bicyclic carbocyclic nucleosides and oligomeric compounds prepared therefrom

Active Publication Date: 2017-05-25
IONIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0011]Provided herein are novel bicyclic carbocyclic nucleosides and oligomeric compounds prepared therefrom. More particularly, the bicyclic carbocyclic nucleosides provided herein, comprise a cycloproponated cyclopentane ring in place of the naturally occurring furanose ring which further includes at least one stereospecific 2′-substituent group. The bicyclic carbocyclic nucleosides can also include further substituent groups in place of one or more hydrogen atoms. The bicyclic carbocyclic nucleosides provided herein are expected to be usef

Problems solved by technology

In certain embodiments, the oligomeric compounds provided herein are expected to hybrid

Method used

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  • Bicyclic carbocyclic nucleosides and oligomeric compounds prepared therefrom
  • Bicyclic carbocyclic nucleosides and oligomeric compounds prepared therefrom
  • Bicyclic carbocyclic nucleosides and oligomeric compounds prepared therefrom

Examples

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Example

Example 1

Synthesis of Nucleoside Phosphoramidites

[0388]The preparation of nucleoside phosphoramidites is performed following procedures that are illustrated herein and in the art such as but not limited to U.S. Pat. No. 6,426,220 and published PCT WO 02 / 36743.

Example

Example 2

Synthesis of Oligomeric Compounds

[0389]The oligomeric compounds used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is well known to use similar techniques to prepare oligonucleotides such as alkylated derivatives and those having phosphorothioate linkages.

[0390]Oligomeric compounds: Unsubstituted and substituted phosphodiester (P═O) oligomeric compounds, including without limitation, oligonucleotides can be synthesized on an automated DNA synthesizer (Applied Biosystems model 394) using standard phosphoramidite chemistry with oxidation by iodine.

[0391]In certain embodiments, phosphorothioate internucleoside linkages (P═S) are synthesized similar to phosphodiester intern...

Example

Example 3

Isolation and Purification of Oligomeric Compounds

[0402]After cleavage from the controlled pore glass solid support or other support medium and deblocking in concentrated ammonium hydroxide at 55° C. for 12-16 hours, the oligomeric compounds, including without limitation oligonucleotides and oligonucleosides, are recovered by precipitation out of 1 M NH4OAc with >3 volumes of ethanol. Synthesized oligomeric compounds are analyzed by electrospray mass spectroscopy (molecular weight determination) and by capillary gel electrophoresis. The relative amounts of phosphorothioate and phosphodiester linkages obtained in the synthesis is determined by the ratio of correct molecular weight relative to the −16 amu product (+ / −32+ / −48). For some studies oligomeric compounds are purified by HPLC, as described by Chiang et al., J. Biol. Chem. 1991, 266, 18162-18171. Results obtained with HPLC-purified material are generally similar to those obtained with non-HPLC purified material.

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Abstract

The present invention provides novel bicyclic carbocyclic nucleosides and oligomeric compounds prepared therefrom. Incorporation of one or more of the bicyclic carbocyclic nucleosides into an oligomeric compound is expected to enhance one or more properties of the oligomeric compound. In certain embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in modulation of normal function of the target RNA. In certain embodiments, bicyclic carbocyclic nucleosides are provided as monomers for use as antivirals.

Description

FIELD OF THE INVENTION[0001]Provided herein are novel bicyclic carbocyclic nucleosides and oligomeric compounds prepared therefrom. In certain embodiments, the bicyclic carbocyclic nucleosides are provided as monomers for use as antivirals. Incorporation of one or more of the bicyclic carbocyclic nucleosides herein into an oligomeric compound is expected to enhance one or more properties of the oligomeric compound such as nuclease stability. In certain embodiments, the oligomeric compounds provided herein are expected to hybridize to a portion of a target RNA resulting loss of normal function of the target RNA. In certain embodiments, hybridization of an oligomeric compound as provided herein to a target pre-mRNA alters its splicing to provide a splice variant. The oligomeric compounds provided herein are also expected to be useful as primers and probes in diagnostic applications.SEQUENCE LISTING[0002]The present application is being filed along with a Sequence Listing in electronic...

Claims

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Application Information

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IPC IPC(8): C12N15/113C07F9/6512
CPCC12N15/113C07F9/6512C12N2310/3231C12N2310/3235C12N2310/321C12N2310/11C12N2310/3341C12N2310/341C12N2310/346C12N2310/351C12N2320/52C12N2310/315C07D239/54C07D473/34C07H19/16C07H19/06C07H21/00C07H23/00C12N15/111C12N2310/3525C12N2320/51A61P31/12
Inventor SETH, PUNIT P.SWAYZE, ERIC E.
Owner IONIS PHARMA INC
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